Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]=1[OH:22])([CH3:11])([CH3:10])[CH3:9].CNC.[H][H]>[Ni].CO.O>[C:18]([C:14]1[CH:15]=[C:16]([CH2:3][C:2]([CH3:1])([CH3:7])[CH2:5][OH:6])[CH:17]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:13]=1[OH:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: [H][H]
Reactant: CC(C)(C=O)CO
Agent: [Ni]
Agent: CNC
Solvent: CO
Solvent: O
Product: CC(C)(CO)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 91 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 185 g (0.9 mol) of 2,6-di-t-butylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. under autogenous pressure of 20-30 bar for 10 h. After the autoclave has cooled and the pressure has been released, 28 g of Raney Ni (0.03 parts based on complete mixture) are added to the reaction mixture and hydrogenation is carried out at 80° C. under 80 bar of hydrogen for 5 h. Workup of the mixture by distillation yields 239 g (91%) of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2,2-dimethylpropanol (boiling point 142°-145° C.; melting point 84°-86° C.).
Reaction SMILES: [CH2:1]=O.[CH3:3][PH:4](=[O:6])[CH3:5].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.N#N>C(O)C>[CH3:3][P:4]([CH2:1][N:10]1[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]1)([CH3:5])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=O
Reactant: C[PH](C)=O
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CP(C)(C)=O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
Formaldehyde (0.954 g, 31.8 mmole, 1.2 eq. 37% WT in water), Dimethylphosphane oxide (2.25 g, 28.8 mmole, 1.09 eq.) and tert-butyl piperazine-1-carboxylate (14.93 g, 26.5 mmole, 1.0 eq.) were dissolved in 20 mL of anhydrous ethyl alcohol. The reaction mixture was sealed in a seal-tube with N2 atmosphere and stirred at 90 Celsius overnight. The reaction mixture was then cooled to room temperature and rotaevaporate to remove volatile components. The light yellow thick oil obtained was purified via column chromatography (elution sequence: 100% hexane-10% EtOAc/hexane-100% EtOAc-10% MeOH/EtOAc/sat.NH3) to yield 1.01 g of the desired compound as white solid. MS (LC/MS): 299.2 [M+Na]
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=2)[N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])=[CH:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:8]4=[N:9][CH:10]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCNCC4)cc3)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 2,2-Dimethyl-1-[2-(4-piperazin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.10 g, 0.203 mmol) in dichloromethane was added 0.042 mL of diisopropylethylamine (0.031 g, 0.244 mmol) and the reaction mixture was subsequently cooled to 0° C. Methane sulfonyl chloride (0.019 mL; 0.028 g, 0.244 mmol) was added via syringe and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted 3 times with dichloromethane. Combined organics were dried over MgSO4, filtered and conc in vacuo. Silica gel chromatography (15→65% EtOAc/hexanes over 30 minutes) afforded 0.1014 g (87% yield) of 1-[2-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil. MS (E/I): 572 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]=[N:10][O:11][CH2:12][C:13]#[CH:14])[CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C(Cl)Cl.O>[CH3:15][NH:16][C:17](=[O:18])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]=[N:10][O:11][CH2:12][C:13]#[CH:14]
Reactant: C#CCON=Cc1cc(Cl)ccc1O
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C#CCON=Cc1cc(Cl)ccc1OC(=O)NC
Yield: 75 %

Procedure:
A solution of 2.4 grams (0.011 mole) of 4-chloro-2-[(2-propynoxyimino)methyl]phenol (Example 1 product), 0.7 gram (0.013 mole) of methyl isocyanate and three drops of triethylamine in 50 ml of methylene chloride was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residual solid. The residue was recrystallized from toluene-hexane to give a solid; mp 97°-100° . The solid was slurried in hot water and collected by filtration. A second recrystallization from toluene-hexane gave 2.2 grams of 4-chloro-2-[(2-propynoxyimino)methyl]phenyl methylcarbamate; mp 99.5°-100.5°.
Reaction SMILES: BrC1C=C(C([N:16]2C[CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=O)OC=1C1C=CC=C(Cl)C=1.[Br:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][C:25]=1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=1.C(N(CC)C(C)C)(C)C>>[Br:23][C:24]1[O:28][C:27]([C:29]([N:16]2[CH2:17][C:18](=[O:22])[NH:19][CH2:20]2)=[O:31])=[CH:26][C:25]=1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(Br)o1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)c(Br)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 23A and the compound from Example 35A. 5 equivalents of N,N-diisopropylethylamine are used. The product is precipitated by the addition of water to the reaction solution. The precipitate is collected by suction filtration, washed with tetrahydrofuran and dried under high vacuum. 587 mg (97% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.O=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O-])=[O:16]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][N:2]1[C:6]2[C:5](=[N:7][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:15]=2[OH:16])[CH:4]=[N:3]1
Reactant: O=C([O-])C1CCCCC1=O
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1ncc2nc3c(c(O)c21)CCCC3
Temperature: 25 °C
Yield: 45.4 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine ((J. Catalan et al., J. Heterocycl. Chem., 1985, 22, 997), 200 mg, 2.06 mmol), 2-oxocyclohexanecarboxylate (351 mg, 2.06 mmol), and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) in toluene (20 ml) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the solvent was removed in vacuo. Diphenyl ether (5 ml) was added to the residue (ca. 300 mg) and the resulting mixture was heated at 240° C. for 40 min. After cooling to room temperature, hexane (2 ml) was added. The precipitate was collected by filtration and washed with dichloromethane to give 190 mg (46%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].Cl[CH2:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:36][CH:37]=1)([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCC(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Product: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (4 g, 12.7 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-diethylamine (3.38 g, 14 mmol). Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:23][C:22]=1[CH3:30]
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccc(B(O)O)cc1C
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1C

Procedure:
The title compound was prepared from the product of Example 65A and 4-methoxy-3-methylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 350.0 (M+H)+, retention time 1.42 minutes.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:12]C1(C)CCCCC1=O.C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.IC(C)C>>[CH:1]([CH:4]1[C:8](=[O:9])[C:7]([CH3:10])([CH3:11])[CH2:6][CH2:5][CH2:12]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1CCC(C)(C)C1=O
Reactant: CC1(C)CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)I
Solvent: CN1CCCN(C)C1=O
Product: CC(C)C1CCCC(C)(C)C1=O
Yield: 78 %

Procedure:
As described in Example 3 for preparation of 5-isopropyl-2,2-dimethylcyclopentanone, from 2,2-dimethylcyclohexanone (12.6 g, 110 mmol), lithium diisopropylamide solution (2 M in THF, 55.0 ml, 110 mmol), DMPU (14.1 g, 110 mmol) and 2-iodopropane (25.5 g, 150 mmol), 6-isopropyl-2,2-dimethylcyclohexanone (13.1 g, 78%) was obtained after standard workup and purification by silica gel FC (pentane/Et2O, 6:4, Rf=0.26).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH:7]=[CH:8][N:9]3[C:14](S(C)(=O)=O)=[N:13][N:12]=[C:10]3[CH2:11][C:5]=2[CH:4]=1.[CH3:21][O-:22].[Na+]>>[CH3:21][O:22][C:14]1[N:9]2[C:10]([CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=3[CH:7]=[CH:8]2)=[N:12][N:13]=1
Reactant: C[O-]
Reactant: COc1ccc2c(c1)Cc1nnc(S(C)(=O)=O)n1C=C2
Agent: [Na+]
Product: COc1ccc2c(c1)Cc1nnc(OC)n1C=C2

Procedure:
The reaction of 9-methoxy-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3,9-dimethoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from aqueous acetone), melting point: 176°-177° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[O:14][C:12]1[C:11]([F:15])=[CH:10][C:9]([F:16])=[C:8]([CH:13]=1)[NH2:7]
Reactant: Nc1cc(O)c(F)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Temperature: 80 °C

Procedure:
To a stirred suspension of cesium carbonate (3.25 g, 10.0 mmoles) in dry DMF (20 mL) was added 5-amino-2,4-difluorophenol (1.00 g, 6.9 mmoles). This solution was heated to 80° C. for 1 hour, and 4-chloro-6,7-dimethoxyquinazoline (1.59 g, 7.1 mmoles) was added and the reaction heated for an additional hour. At the end of this time the reaction was poured into water (200 mL) and extracted with two portions (200 mL) of ethyl acetate. The extracts were combined and dried over MgSO4. Filtration and concentration afforded 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline as a crude red oil. Purification by silica gel chromatography eluting with an ethyl acetate/hexane gradient, 30%-70% over 70 minutes gave a slightly impure oil containing DMF. This oil was crystallized using ethyl acetate hexane to give a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[CH:6][C:2]2=[N:1][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccccc2)nc2cc[nH]n12

Procedure:
Compound 24 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-pyrazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) benzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH3:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]=[C:24]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]([C:3]([O:2][CH3:1])=[O:13])[CH3:5])=[CH:7][CH:8]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C(C)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(C)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under inert gas atmosphere 3.43 g (2.97 mmol) Pd(PPh3)4 are added to 17.2 g (59.4 mmol) 2-(4-iodo-phenyl)-propionic acid methyl ester (Bioorg. Med. Chem. Lett. 2010, 20, 896), 20.2 g (65.3 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 18.9 g (178 mmol) sodium carbonate in 200 mL 1,2-dimethoxyethane and 30 mL water. The mixture is stirred for 2 h at 100° C. and for additional 12 h at 80° C. After that time, water is added and the mixture is extracted with EtOAc (3×). The combined organic layers are washed with water (2×) and brine and dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; heptane:EtOAc gradient 100:0->60:40).
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])C.Cl[C:15]1[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[CH:25][C:16]=1[C:17]([CH2:19][C:20]([O:22]CC)=[O:21])=[O:18].[O-2].[Mg+2].Cl>C(OCCO)CCC.O.C(O)C>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[N:5]1[C:15]2[C:16](=[CH:25][C:26]([F:30])=[C:27]([Cl:29])[CH:28]=2)[C:17](=[O:18])[C:19]([C:20]([OH:22])=[O:21])=[CH:4]1
Reactant: CCOC=Nc1ccc(F)cc1F
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Solvent: O
Solvent: CCCCOCCO
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Temperature: 110 °C
Yield: 78.1 %

Procedure:
60 ml of ethylene glycol monobutyl ether, 37 g of N-(2,4-difluorophenyl)-formimino ethyl ether and 50 g of ethyl 2,4-dichloro-5-fluoro-benzoylacetate were heated at 60° to 65° C. for 5 hours. Ethanol and a little solvent were stripped off under 20 mbar. The mixture was then diluted with 150 ml of ethylene glycol monobutyl ether, 12 g of magnesium oxide were added and the mixture was heated at 110° C. for 10 hours. For working up, the reaction mixture was poured into a mixture of 150 ml of water and 50 ml of 37% strength aqueous hydrochloric acid, heated at the boiling point for 5 hours and diluted with water and the precipitate was filtered off with suction and washed with water and 2-propanol to give 49.5 g of 99% pure N-(2,4-difluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. This corresponds to 70% of theory, based on the formimino ether employed.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH:11]=[CH2:12].C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([NH:20][C:3](=[O:5])[CH:2]2[O:1][CH:6]2[C:7]([O:9][CH2:12][CH:11]=[CH2:10])=[O:8])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: C=CC[K]
Agent: O=C(Cl)C(=O)Cl
Product: C=CCOC(=O)C1OC1C(=O)Nc1ccccc1
Yield: 50.7 %

Procedure:
Following the procedure of Example 1, monoallyl potassium epoxysuccinate (2.1 g) was successively treated with oxalyl chloride (1.26 g) and aniline (1.86 g) to give 1.24 g of allyl N-phenyl-2,3-epoxysuccinamate (Compound No. 30) as colorless needles melting at 32° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH:12]2[C:16](=O)[CH2:15][N:14]([CH3:18])[C:13]2=[O:19])[CH:11]=1.O.Cl>ClC1C=CC=CC=1.CCCCCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]3[CH2:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[C:10]=2[CH:11]=1
Reactant: CN1CC(=O)C(c2cc(Cl)ccc2Oc2ccccc2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CN1CC2=C(C1=O)c1cc(Cl)ccc1Oc1ccccc12
Temperature: 98 °C
Reaction time: 1 h

Procedure:
Anhydrous aluminium chloride (5 g) was added to a reaction mixture containing 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione (1 g) in monochlorobenzene (1 mL) at ambient temperature. The reaction mixture was stirred at about 98° C. for about 1 hour, then cooled to ambient temperature. A mixture of water and concentrated hydrochloric acid (50 mL:5 mL) was added slowly. The contents were stirred for about 30 minutes. Hexane (50 mL) was added. The contents were stirred for about 1 hour, filtered, washed with hexane (15 mL) and dried in air at about 30° C. for about 15 hours to obtain 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo [2,3:6,7] oxepino [4,5-c]pyrrol-1-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCCCN
Solvent: c1ccncc1
Product: O=C(NCCCCCCCNC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 1,9-diazanonane (13 g, 0.1 mol) in pyridine (200 mL) and cool to 0° C. Add, by dropwise addition, benzoyl chloride (31 g, 0.22 mol) and stir overnight. Extract into chloroform, wash with water, 5% hydrochloric acid, 5% sodium hydroxide, water and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 1,9-bis(benzoyl)-1,9-diazanonane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)(=[O:28])=[O:27])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Nc2cccc(-n3ncc4c(N)ncnc43)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 4-methoxybenzenesulphonylchloride (30 mg, 1.0 eq, 0.15 mmol) and diisopropylethylamine (25 μl, 1.0 eq, 0.15 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant solid was purified by semi-preparative HPLC to yield the title compound as a white solid (30 mg, 0.08 mmol, 52%). LCMS: [M+H]+=397, Rt=1.68 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]#N)=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-:17].[Na+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:9](=[O:17])[CH2:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH3:22]
Reactant: O=C([O-])O
Reactant: CCO
Reactant: Cc1ncccc1CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cccnc1C

Procedure:
790 mg (5.98 mmol) of the compound from Example 38A are initially introduced into 10 ml ethanol, 4 ml concentrated sulfuric acid are added slowly and the mixture is heated under reflux for 6 h. After cooling, the mixture is neutralized with 6.00 g sodium bicarbonate and saturated sodium bicarbonate solution. The aqueous phase is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is reacted without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:47])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(OC)cc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound was obtained in 81% purity by HPLC. MS(ESI+): m/z=518.